Development of a targeted TGF-b therapeutic that selectively blocks lung fibrosis in idiopathic pulmonary fibrosis (IPF) patients

综合本项目摘要/摘要第一阶段NHLBI IPF是一种慢性、不可逆转的纤维性肺部疾病，由反复损伤驱动，导致进展性 变得僵硬，最终导致肺功能丧失。每年有13万名IPF患者，5年死亡率为 80%，对新疗法的需求很大。到目前为止，传统疗法并没有阻止疾病的发展。 进步。最近批准了两种IPF新药：抗纤维化药物吡非尼酮和9tedanib，a 酪氨酸激酶抑制剂，但两者都只能适度延缓疾病的进展。转化生长因子−是主要的驱动因素之一 IPF患者的纤维化，由于其在肺中的水平升高和持续时间延长。在细胞层面上，转化生长因子−驱动 激活的肌成纤维细胞是疾病的主要肇事者，可以过度产生胶原并增加纤维连接蛋白 沉积在细胞外基质(ECM)中，逐渐阻碍肺功能。抑制转化生长因子−- 介导性纤维化有可能阻止甚至逆转IPF患者的疾病。然而，转化生长因子−被广泛应用。 表达并在维持组织动态平衡方面起着重要作用。因此，尽管转化生长因子−抑制剂具有 尽管人们对治疗纤维化的兴趣很大，但由于有大量的宿主(即， 心脏)毒性。更安全的转化生长因子−抑制剂选择性阻断特发性肺纤维化患者的纤维化，但仍能保护宿主 组织，将提供有区别的治疗选择，以满足这一重大的未得到满足的需求。在这个SBIR奖中，我们 正在开发一种一流的抗体药物结合物(Adc)平台，选择性地抑制转化生长因子−驱动 特发性肺纤维化患者的临床表现。在目标1中，我们将开发我们的新型ADC疗法(SYN301)并演示 特发性肺纤维化患者成纤维细胞纤维化的抑制作用，通过前胶原的减少来评估 和α-平滑肌肌动蛋白的体外表达是纤维化疾病的临床标志物。在目标2中，我们将评估 SYN301在行业标准的体内博莱霉素性肺纤维化模型中的疗效。SYN301将 通过肺组织病理学检测，评估其对疾病进展和肺纤维化的抑制作用， 炎性细胞浸润、胶原沉积和BALF免疫细胞组成。我们预计SYN301 与标准护理疗法相比，在体外和体内都将减少纤维化的标记物。SYN301是一种 首屈一指的治疗将安全地阻止转化生长因子−诱导的特发性肺纤维化患者。这是第一个ADC分子 被开发为选择性地阻断转化生长因子−导致的纤维化。此外，SYN301还可用于 与目前的纤维化治疗相结合，以提高患者的总体应答率。组织纤维化是一种广泛的 在多种其他疾病中传播问题，如NASH、肾脏纤维化和心脏纤维化，其中转化生长因子−是 也是导致驾驶疾病的重要因素。因此，我们的治疗平台广泛适用于多种类型的纤维化 疾病，为最需要的患者提供新的治疗选择。

Synthis Project Summary/Abstract Phase I NHLBI IPF is a chronic, irreversible fibrotic lung disease driven by repeated injury, resulting in progressive stiffening and ultimately, loss of lung function. With 130,000 IPF patients annually and a 5 year mortality rate of 80%, there is significant need for new therapies. To date, conventional therapies have not halted disease progression. Recently 2 new IPF drugs were approved: pirfenidone, an anti-fibrotic agent and, nintedanib, a tyrosine kinase inhibitor, but both only modestly delay disease progression. TGF− is one of the key drivers of fibrosis in IPF patients, due to its elevated and prolonged levels in the lung. On a cellular level, TGF− drives activated myofibroblasts, the major perpetrators of disease, to over-produce collagen and increase fibronectin deposition in the extracellular matrix (ECM), which progressively blocks lung function. Inhibition of TGF−- mediated fibrosis could potentially stop or even reverse disease in IPF patients. However, TGF− is widely expressed and has essential roles in maintaining tissue homeostasis. Thus, although TGF− inhibitors are of significant interest to treat fibrosis, development of therapies has been hindered due to significant host (i.e., cardiac) toxicity. Safer TGF− inhibitors that selectively block fibrosis in IPF patients, but still protect host tissues, would provide differentiated treatment options to fill this significant unmet need. In this SBIR award, we are developing a first in class antibody drug conjugate (ADC) platform to selectively inhibit TGF− driven fibrosis in IPF patients. In Aim 1, we will develop our novel ADC therapeutic (SYN301) and demonstrate inhibition of fibrosis in fibroblasts derived from IPF patients, as assessed by a decrease in procollagen expression and alpha smooth muscle actin in vitro, clinical markers of fibrotic disease. In Aim 2, we will assess the efficacy of SYN301 in an industry standard, in vivo model of bleomycin induced lung fibrosis. SYN301 will be assessed for inhibition of disease progression and lung fibrosis as measured by lung histopathology, inflammatory infiltrates, collagen deposition and BALF immune cell composition. We anticipate that SYN301 will reduce markers of fibrosis both in vitro and in vivo, compared to standard of care therapies. SYN301 is a first in class therapy that will safely block TGF− induced fibrosis in IPF patients. It is the first ADC molecule being developed to selectively block TGF− driven fibrosis. Moreover, SYN301 could also be used in combination with current fibrosis therapies, to increase overall patient response rates. Tissue fibrosis is a wide spread issue in multiple other diseases, such as NASH, kidney fibrosis and cardiac fibrosis, of which TGF− is also instrumental in driving disease. Thus, our therapeutic platform is widely applicable to fibrosis in multiple diseases, providing novel therapeutic options for patients that need it the most.